Elevated extracellular K(+) concentrations inhibit N-methyl-D-aspartate-induced Ca(2+) influx and excitotoxicity.

Although extracellular [K(+)] ([K(+)](E)) is highly elevated during brain ischemia, in vitro studies aimed at explaining the mechanisms of excitotoxicity have been conducted at low [K(+)](E). Whether high [K(+)](E) affects excitotoxicity has not been formally addressed. Therefore this study, using digital fluorescence microscopy, tested how the elevation of [K(+)](E) from 5.6 to 60 mM affects N-methyl-D-aspartate (NMDA)-induced Ca(2+) and Na(+) influx, plasma membrane (PM) potential, mitochondrial Ca(2+) load, and viability of primary cultures of rat cerebellar granule cells. High [K(+)](E) curtailed the NMDA-induced Ca(2+) and Na(+) influx and mitochondrial Ca(2+) overload, and prevented neuronal death. Surprisingly, the inhibitory effect of high [K(+)](E) on the NMDA-induced Ca(2+) influx could not be linked to depolarization of the PM. Apparently, the PM of cerebellar granule cells exposed to NMDA was more depolarized at low than at high [K(+)](E), probably because the NMDA-induced Na(+) influx was greatly enhanced when the extracellular [Na(+)]/[K(+)] ratio was increased. When this ratio was small, i.e., at high [K(+)](E), the NMDA-induced increase in cytoplasmic [Na(+)] was suppressed, preventing Ca(2+) influx via the reverse operation of the Na(+)/Ca(2+) exchanger, which may explain the inhibitory effect of high [K(+)](E) on NMDA-induced Ca(2+) influx and excitotoxicity.